α1－アンチトリプシン欠乏症

BACKGROUND: Alpha-1 Antitrypsin Deficiency (AATD) is a rare, underdiagnosed genetic disorder caused by pathogenic variants of the SERPINA1 gene, which can lead to reduced levels and/or dysfunctional forms of the Alpha-1 Antitrypsin (AAT) protein. Accurate AATD diagnosis is critical due to its implications for pulmonary and hepatic health. However, diagnostic practices vary across laboratories, particularly in the detection and reporting of rare variants. This study aimed to evaluate the consistency and reliability of AATD diagnostic testing across European laboratories through a non-commercial external quality assessment (EQA)-like initiative. METHODS: Seven European laboratories participated in six assessment rounds between 2019 and 2021. Each round involved blinded analysis of serum and dried blood spot (DBS) samples using local standard operating procedures. Tests included AAT and C-reactive protein quantification, isoelectric focusing for AAT phenotyping, and genotyping/sequencing for common and rare SERPINA1 variants. Interrater agreement was assessed using Fleiss' kappa statistic. Allele error rates were calculated for each variant and Kruskal-Wallis tests were used to compare AAT concentrations across laboratories. RESULTS: For common variants (M [normal], S [p.E288V], and Z [p.E366K]), interlaboratory concordance was high, with Fleiss' kappa values indicating almost perfect agreement (0.85-1.00). Genotyping and sequencing error rates for these variants were zero. However, detection of rare variants (e.g., MProcida [p.L65P], MHeerlen [p.P393L], and MWurzburg [p.P393S]) was inconsistent, with error rates ranging from 0.14 to 0.29. Sequencing was more effective than phenotyping or simple genotyping for rare variant identification. AAT concentration measurements were generally consistent across laboratories, though DBS samples showed more variability. Reporting nomenclature also varied widely, highlighting the need for standardisation. CONCLUSIONS: This initiative demonstrated strong interlaboratory agreement in detecting common AATD variants but revealed challenges in identifying and reporting rare variants. The findings support the need for SERPINA1 sequencing in AATD diagnostics and the adoption of standardised nomenclature. Centralised testing in validated reference laboratories is also recommended to ensure diagnostic accuracy and consistency across Europe.

Alpha-1 antitrypsin deficiency (AATD) is a hereditary disorder that reduces a key lung-protective protein, predisposing individuals to early-onset emphysema. Multiple Endocrine Neoplasia type 2B (MEN2B), caused by RET gene mutations, is a rare syndrome characterised by aggressive medullary thyroid carcinoma and pheochromocytoma. Coexistence of MEN2B and AATD has not previously been reported. A 32-year-old woman with a history of medullary thyroid carcinoma and prior total thyroidectomy presented with severe dyspnea, generalised edema and weakness after discontinuing levothyroxine. She was tachycardic and hypoxemic, with wheezing and bilateral crackles. Laboratory evaluation showed leukocytosis, thrombocytosis, electrolyte abnormalities and markedly reduced alpha-1 antitrypsin levels. Chest CT revealed bilateral cystic and emphysematous changes, and spirometry confirmed severe obstructive disease. Supportive therapy and symptom-directed management improved her respiratory status. The diagnoses of MEN2B and AATD were made based on clinical features, biochemical findings and imaging results, as confirmatory genetic testing was not available according to sanction. This case highlights the extremely rare coexistence of MEN2B and AATD. Overlapping manifestations contributed to delayed recognition. Clinicians should consider rare genetic conditions when common diagnoses do not fully explain a patient's presentation.

Lung volume reduction (LVR) has evolved over nearly a century as a therapeutic strategy for advanced emphysema, reflecting cycles of innovation, skepticism, and renewed acceptance informed by advances in physiology, imaging, and patient selection. Early surgical approaches-including bullectomy, intracavitary drainage techniques, and nonselective lung resection-laid the conceptual groundwork but were limited by high morbidity and inconsistent outcomes. The modern era of LVR was catalyzed by refined surgical techniques and culminated in the National Emphysema Treatment Trial, which established the critical importance of phenotype-based patient selection. Parallel advances in bronchoscopic lung volume reduction (BLVR) expanded treatment options, particularly through the development of endobronchial valves (EBVs), coils, thermal vapor ablation, and biologic approaches. Among these, EBVs have achieved the strongest evidence base and regulatory approval, supported by improved understanding of collateral ventilation and fissure integrity. More recently, minimally invasive surgical approaches, robotic-assisted techniques, hybrid procedures, and expanded indications-including lower-lobe disease, very severe airflow limitation, and alpha-1 antitrypsin deficiency (AATD)-have further broadened the therapeutic landscape. LVR also plays an evolving role as an adjunct to lung transplantation, both as a bridge and for management of native lung hyperinflation (NLH). This narrative review traces the historical arc of LVR, highlighting how past successes and failures inform contemporary practice. As technology advances, multidisciplinary evaluation and increasingly personalized, data-driven decision-making will be central to optimizing outcomes and guiding the future of emphysema management.

The Cystic Fibrosis Foundation organised a multidisciplinary committee to develop this Position Paper to outline current knowledge and best practices in reproductive health care for individuals with cystic fibrosis. Working groups reviewed the literature and provided relevant guidance on reproductive health services, fertility, contraception, preconception and pregnancy, and cystic fibrosis transmembrane conductance regulator (CFTR) modulator exposure in utero and during lactation. Findings included: (1) reproductive health-care provision should be standardised, and education should begin at cystic fibrosis diagnosis and revisited annually; (2) contraception is safe overall, but underutilised in those with cystic fibrosis compared with the general population; (3) fertility might be improving with CFTR modulators for females with cystic fibrosis, but not for males with cystic fibrosis-assisted reproductive technologies are still required for males to achieve biological parenthood; (4) pregnancy requires close monitoring and unique screening for diabetes; and (5) CFTR modulator exposure in utero has implications for infant monitoring and cystic fibrosis screening results in newborns.